BTX-1188 Undergoing Evaluation in AML, Solid Tumors After Showing Promise in Preclinical Data

BTX-1188 could prevent systemic inflammatory dose-limiting toxicities that are usually attributed to pure GSPT1 degradation due to its immunomodulatory properties from the IKZF1/3 degradation.

Preclinical data demonstrated potential for using the first-in-class oral molecular glue BTX-1188 in patients with solid tumors or acute myeloid leukemia (AML) and greater sensitivity in MYC dependent/high disease and is now being investigated in phase 1 clinical trials, according to a poster presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.1

BTX-1188 could prevent systemic inflammatory dose-limiting toxicities that are usually attributed to pure GSPT1 (G1 to S phase transition 1) degradation due to its immunomodulatory properties from the IKZF1/3 (Ikaros/Aiolos) degradation. The FDA granted an Investigational New Drug Application for BTX-1188 and a phase 1 trial (NCT05144334) was initiated to assess the safety and toxicity profile, as well as the pharmacokinetics and preliminary activity, of the drug in hematologic and solid malignancies.2

The translation termination factor GSPT1 and transcription factor IKZF1/3 are required for the development and differentiation of lymphocytes and the modulation of cytokines.1 “BTX-1188…degrades GSPT1 and Ikaros/Aiolos, or IKZF1 and IKZF3, thereby resulting in inhibition of protein translation and in modulation of cytokines, respectively,” Aparajita Hoskote Chourasia, PhD, said in her presentation.

For the preclinical study, investigators gave athymic or BALB/c nude mice xenograft models a vehicle or BTX-118. They measured cell viability in cells treated with BTX-118 and patient samples by CellTiter-Glo 2.0 assay. Immunoblots of protein lysates from cells treated with DMSO (dimethyl sulfoxide) or BTX-118 were used to analyze substrate degradation and apoptosis profiles. Interleukin (IL)-2 or lipopolysaccharide (LPS)-induced measurements of inflammatory cytokines upon DMSO or compound treatment were taken after human peripheral blood mononuclear cells (PBMCs) were stimulated with αCD3.

In addition to rapid and deep degradation of GSPT1 and IKZF1/3, BTX-1188 also an inhibitor of MYC in multiple cell lines. The AML cell line MV-4-11 showed significant GSPT1 and IKZF1/3 degradation after 2 hours of treatment with 100 nM of BTX-1188 (P < 1 × 10-5) and 6 hours with 3 nM (>90% of GSPT1), respectively, in a proteomics and immunoblot analysis. According to the study investigators, this indicates rapid and potent neosubstrate degradation.

“Our data show that it has single-digit nanomolar DC50 for the Cereblon neosubstrates both in AML and in lymphoma, and that it also significantly inhibits MYC at low nanomolar concentrations,” Chourasia explained.

The investigators also observed significantly lower levels of GSPT1 and sustained apoptosis after treatment with 30 nM for 6 hours followed by washout, similar to what has been seen with PARP cleavage for up to 24 hours. BTX-1188’s durability in degrading GSPT1 expresses as low nanomolar IC50 even though there was 72-hour period of compound washout.

Inhibition of proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α, and induction of IL-2 by LPS and αCD3-stimulated PBMCs demonstrates BTX-1188 immunomodulatory properties. “These immunomodulatory properties are expected to improve clinical outcomes and reduce toxicities associated with selective GSPT1 degradation [without IKZF1/3 degradation], thus expanding its therapeutic window,” Chourasia said.

For cancer cell lines such as primary human patient AML samples (IC50 range, 0.4-1.5 nM) and MYC-dependent and non-MYC dependent lines (IC50 range, 0.5-20 nM), BTX-1188 is functionally cytotoxic. This includes samples from disease that is relapsed/refractory, cytarabine resistant, or venetoclax (Venclexta) resistant.

In vivo efficacy models which received daily or intermittent dosing of BTX-1188 also showed durability of GSPT1 degradation and sustained apoptosis, further indicating significant and sustained antitumor activity.

“Based on this data, our drug has entered phase 1 clinical studies for both solid tumors, as well as AML,” Chourasia concluded.

The sequential dose-escalation study currently enrolling patients to investigate BTX-1188 is multicenter, open label, and nonrandomized. The approximately 168 eligible patients with either AML, advanced solid tumors, or non-Hodgkin lymphoma will receive 1 of 7 doses of BTX-1188. Evaluation of treatment-emergent adverse events and determination of the recommended phase 2 dose are the primary end points of the trial.


1. Chourasia AH, Majeski H, Pasis A, et al. BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors. J Clin Oncol. 2022;40(suppl 16):7025. doi:10.1200/JCO.2022.40.16_suppl.7025

2. BioTheryX receives IND clearance from FDA to proceed with phase 1 study of BTX-1188, a molecular glue, for the treatment of hematologic and solid malignancies. News release. PRNewswire. Published November 2, 2021. Accessed June 3, 2022.